As compounds that exhibit an inhibitory effect on activated blood coagulation factor X [which is also referred to as an “FXa (activated Factor X)”], for example, N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethanediamide [hereinafter also referred to as “compound (X)”] represented by the following formula (X):
or a salt thereof, or a hydrate thereof, ora p-toluenesulfonic acid monohydrate of compound (X), which is represented by the following formula (X-a):
are known (see, for example, Patent Literatures 1 to 4).
For example, Patent Literature 6 discloses a method for producing compound (X) that is an FXa inhibitor or a pharmacologically acceptable salt thereof, or a hydrate thereof. As shown in the following [Scheme A], the method for producing compounds (X and X-a) disclosed in Patent Literature 6 comprises: producing compound (A-7) that is an azide form from compound (A-5) via compound (A-6) that is a mesyloxy form; then reducing the compound (A-7) to obtain compound (1a) that is an amino form; then treating the compound (1a) with oxalic acid to obtain compound (1); then treating the compound (1) with ethyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate monohydrochloride (A-8) in the presence of a base to produce compound (A-9), and further performing several steps after production of the compound (A-9). Patent Literature 6 discloses that compound (1a) and compound (1) that is an oxalate of the compound (1a) are important as production intermediates in the production of compound (X) that is an FXa inhibitor.
wherein Boc represents a tert-butoxycarbonyl group; and Ms represents a methanesulfonyl group.
However, the method for producing compound (1 or 1a) disclosed in Patent Literature 6 has the following problems (a) and (b).
(a): The use of compound (A-7) having a potentially harmful azide group as an intermediate. Specifically, the use of compound (A-7) as an intermediate is problematic in that mass production of compound (A-7) that is an azide form requires the use of a large amount of an azide, which is a dangerous reagent, as a reaction reagent, in that mass production of compound (1) that is an amino form requires reduction of a large amount of compound (A-7) that is an azide form in the presence of a heavy metal catalyst such as Pd in pressure-resistant equipment and the like, and in that it is necessary to control mixing of the heavy metal into the product.(b): In the azidation reaction (the nucleophilic substitution reaction of an azide group) in the production of compound (A-7) that is an azide form, in addition to the desired compound (A-7), a compound represented by the following formula (A-7-trans) that is a trans-isomer substituted in the trans-configuration with respect to the adjacent tert-butoxycarbonylamino group:
is generated as a stereoisomer at a percentage of approximately 10% to 15%. The subsequent reduction reaction progresses while the configuration is retained, and compound (A-7-trans) that is an azide form gives a compound (1a-trans) that is an amino form as a result of the reduction reaction. Accordingly, in order to obtain compound (1a) of interest in the cis-configuration at high purity, it is necessary to isolate and purify the desired compound (A-7) at the stage of the azide form, and therefore, a purification step using silica gel column chromatography or the like has been required (see, for example, Patent Literatures 1 to 5). On the other hand, in Patent Literature 6, a mixture of compound (1a) that is an amino form and the compound (1a-trans) that is a trans-isomer of the compound (1a) is treated with oxalic acid to obtain compound (1) that is an acid-added salt with the oxalic acid, so that the compound is substantially obtained in the form of a single cis-isomer.
However, as a method for producing compound (1) and compound (1a) that are important intermediates in the production of compounds (X) and (X-a) that are FXa inhibitors, only the aforementioned method via compound (A-7) that is an azide form, which causes many problems [(a) and (b)] as described above, is known so far (see, for example, Patent Literatures 1 to 6).